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Inhibitors - What You Should Know
In Hemophilia A and B patients being treated with anti-hemophilic
factor products, the development of inhibitors is an ongoing
concern. Inhibitors are the result of an immune response to the
introduction of foreign factor proteins. Mistaking the factor
proteins as infectious, the immune system destroys the proteins
needed to treat a bleed, resulting in the infusion being
ineffective, the bleeding continuing, and the factor being wasted.
Inhibitors cannot be prevented and may occur at anytime. The
treatment of an inhibitor is costly, time consuming, and demanding.
Individuals with Hemophilia A develop inhibitors more often than
those with Hemophilia B, though the reasons why are unclear.
|For those with...
||This percent of the population will
develop an inhibitor:
|Severe Hemophilia A
||Up to 25%
|Severe Hemophilia B
||1.5 - 5%
|Mild or Moderate Hemophilia
People who have a family history of inhibitors, patients with
certain genetic mutations, and minorities with hemophilia are
statistically at a higher risk to develop inhibitors. Children under
the age of 5 are also at an increased risk. Most inhibitors occur
within 5 to 50 days of treatment with factor.
The titer level of an inhibitor is measured in Bethesda Units
||People with this level are called .
|0.5 to 5 BU
Inhibitor patients fall into three categories:
- Patients with inhibitors which are transient and disappear
- Patients with inhibitors which disappear with immune
- And, patients with inhibitors which are persistent and
Transient inhibitors may be fairly common but infrequently
diagnosed because they do not noticeably affect the efficacy of
Although a blood test for inhibitors is usually performed
annually by the Hemophilia Treatment Center, one should also be
performed if factor replacement is ineffective or prior to surgery.
|The goal of treatment for a hemophilia patient with an inhibitor
is two-fold: to control the bleeding episode and to eliminate the
inhibitor. The approach to treatment is dependent upon the titer
level of the inhibitor, how the inhibitor level responds to an
infusion, and the severity of the bleed
Controlling Bleeding Episodes
ypassing agents are commonly used to stop a bleeding episode in
inhibitor patients. The body uses two molecular pathways to
promote coagulation, called the intrinsic and extrinsic pathways.
The intrinsic pathway utilizes factors VIII and IX (among others).
The extrinsic pathway can be strengthened to compensate for the
deficiencies of the intrinsic pathway found in Hemophilia A or B by
administering a bypassing agent. Two products are available in the
US for this purpose:
- NovoSeven recombinant FVIIa
- Feiba VH anti-inhibitor coagulant complex
These products differ in the required dosage level and interval
as well as the method of viral purification used in their
preparation. To compare these products, see our
product comparison chart here. Course of treatment must be
determined on an individual basis.
A low responder whose inhibitor level doesnt rise above 5 BU in
response to an infusion of a factor concentrate may require a larger
dose of factor in order to overwhelm the inhibitor. Dosage must be
closely clinically monitored.
In a high responder whose inhibitor level rises above 5 BU only in
response to an infusion of factor concentrate, the effectiveness of
factor products in treating a bleed is greatly reduced. Factor is
usually administered to these patients in the event of a severe
bleed that is life or limb threatening. Bypassing agents such as
NovoSeven and Feiba VH are commonly used in the treatment of
bleeding episodes in these patients.
In the treatment of a high responder whose inhibitor level is
consistently above 5 BU even without exposure to a factor product,
the use of factor concentrates is largely ineffective and may
promote an anamnestic response, resulting in an increased inhibitor
level. NovoSeven or FEIBA are available options used to control
bleeding episodes in these patients.
Elimination of Inhibitors
Some inhibitors are transient and disappear without treatment. In
patients with persistent inhibitors, a course of treatment called
Immune Tolerance Induction is common. Immune Tolerance Induction
involves overwhelming the immune system through administering a high
dosage of factor on a regular basis, usually at least several days
per week. The course of treatment may span several years, making it
time consuming and costly.
The effectiveness of Immune Tolerance Induction is determined by
many factors. It is most effective in patients with a lower titer of
inhibitors who do not
miss any treatments. Repeated attempts at Immune Tolerance
Induction often produce less successful results each subsequent
attempt. Patients who begin with much higher titers have a lower
success rate with Immune Tolerance Induction. Certain genetic
mutations can also reduce its success.
For Further Information
To learn more about inhibitors, visit either of the following on
National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/)
National Hemophilia Foundation (http://www.hemophilia.org/)
Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in
haemophilia A patients a review of recent studies of recombinant
and plasma-derived factor VIII concentrates. Haemophilia
1999; 5: 145-154.
Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy,
dosing regimens and safety in patients with congenital and acquired
factor VIII or IX inhibitors. J Thromb Haemost 2004; 2:
Lacroix, R.N., Sylvie, Nora Schwetz, R.N., Andrea Pritchard,
R.N., Kathy Mulder, B.P.T., and Nichan Zourikian, B.P.T. All
About Inhibitors. 1999, Canadian Hemophilia Society.